HPV vaccination: balancing facts
Recent history demonstrates that vaccination of children to prevent future disease can induce an often‐acrimonious debate. Add into this mix a vaccine aimed at adolescent girls to prevent an infection acquired through sexual contact, to prevent a disease that causes harm in adulthood, and the scene is set for a predictable controversy.
These debates are often presented in the interests of ‘balance’. However, ‘balance’ is both a noun (a situation where elements are equal, or in the correct proportions) and a verb (to offset or compare the value of one thing with another). Synonyms for the verb ‘balance’ include ‘evaluate’, ‘compare’, ‘consider’, and ‘appraise’. Cochrane is founded on the principles of balance (verb), and Cochrane researchers have worked to evaluate, consider, and appraise the evidence about human papillomavirus (HPV) vaccination to prevent cervical cancer.
Cervical cancer is the fourth most common cancer in women worldwide. It is estimated that in 2012, approximately 528,000 women developed cervical cancer and that 266,000 died from the disease. This is a real‐world tragedy. It often affects young women, leaving children without their mothers. The peak age of incidence of cervical cancer in the UK is now 25 to 29 years of age, and only two‐thirds of women in this age group have regular screening. However, the vast majority of cervical cancer deaths occur in regions of the world where women lack access to cervical screening programmes, which are expensive and labour‐intensive to run, requiring high‐level co‐ordination of care to deliver effectively across a population.
Cervical screening programmes aim to identify and treat women who have the precursor lesion of cervical cancer: cervical intra‐epithelial neoplasia (CIN). One in three women who have the most severe grade of CIN (CIN 3) will go on to develop cervical cancer if left untreated for several years. Women with high‐grade CIN can be treated by removal of the abnormal tissue from the cervix, a procedure commonly called large loop excision of the transformation zone (LLETZ). Cervical screening has significantly reduced the rate of cervical cancer in the UK since the 1990s, demonstrating what a screening programme can achieve when the natural history of the disease is understood, and where there is an effective screening test for a pre‐malignant stage of disease and a relatively simple treatment to prevent disease progression. However, cervical screening is not completely benign. Women may find screening and treatment of CIN distressing, and LLETZ can affect future pregnancy outcomes by increasing the risk of late miscarriage and premature delivery.[6-8]
The aetiology of cervical cancer and the natural history of its development are well understood. High‐risk types of HPV are the main cause of almost all cervical cancers, with HPV types 16 and 18 together responsible for 70% of cervical cancer worldwide. Although almost everyone will be exposed to HPV, most will clear the virus through an immune response within six to 18 months. In a minority of women, the virus infection is not cleared, and they can go on to develop CIN and then cervical cancer over several years.
HPV is a DNA virus, made up of a protein shell (capsid) containing viral DNA. The proteins that make up the capsid, when produced artificially, self‐assemble into empty capsids, forming virus‐like particles (VLPs). VLPs do not contain viral DNA and so cannot cause an active infection. VLPs stimulate an immune response, producing antibodies that bind to the virus shell, blocking the receptors that mediate infection. By priming the immune system with VLPs, the body is able to mount a more robust response to subsequent natural exposure to HPV, thereby reducing the likelihood of infection and its consequences. Vaccines have been developed based on combinations of VLPs for HPV types 16 and 18, plus types 6 and 11 (which cause genital warts), or newer combinations of up to nine different VLPs.
Cervical cancer can take many years to develop following the initial HPV infection, so waiting to see to what extent HPV vaccines could reduce cancer rates would take several decades and involve trials of millions of women. Reduction of development of high‐grade CIN is therefore thought to be a valid, medium‐term outcome that will predict whether vaccination can reduce cervical cancer rates. Furthermore, reduction in CIN rates alone could lead to clinically meaningful outcomes, reducing pain, distress, and poor obstetric outcomes.
In their Cochrane Review, Arbyn and his team have combined the results of 26 randomized control trials of HPV vaccination to prevent cervical cancer. These trials included 73,428 women and adolescent girls, across a variety of populations. The authors looked separately at the effects of vaccination in those who at baseline had no evidence of HPV DNA, HPV 16/18 specifically, or participants unselected for baseline DNA status. They also looked at whether the results of studies done in younger women (aged under 26 years of age) differed from those in older women (aged 24 to 45 years).
The results for women known to be negative for HPV16/18 are interesting in a research context and tell us that HPV vaccines reduce high‐grade CIN caused specifically by HPV16/18 in younger women from 113 to 6 per 10,000 women. This would mean that we need to vaccinate about 62 young women who are known to be free of HPV16/18 for one to be protected against high‐grade cervical lesions. However, in a real‐world setting it is unlikely that HPV testing would be performed prior to vaccination. In adolescent girls and young women (15 to 26 years) who were unselected on the basis of HPV exposure, vaccination reduced high‐grade CIN caused specifically by HPV16/18 from 341 to 157 per 10,000 women, and any high‐grade CIN from 559 to 391 per 10,000 women. The corresponding numbers needed to vaccinate for these outcomes are 54 and 68, respectively.
In women aged over 24 years (the population most likely to have already been exposed to HPV) the vaccines do not confer similar benefits. The risk of any high‐grade CIN is similar between unvaccinated and vaccinated older women, although CIN caused specifically by HPV 16/18 is probably slightly lower following HPV vaccination.
Follow‐up periods in the studies in the review ranged between 1 and 8.5 years, with most around 3 to 5 years. Over time, the vaccine may have even more of an effect in those not exposed prior to vaccination, since high‐grade CIN can take several years to develop following initial HPV exposure.
While we can be confident that rates of serious adverse events and miscarriage are similar between vaccinated and unvaccinated women, other rare harms are difficult to determine in randomized controlled trials, even those that have recruited tens of thousands of participants. We now need to look to follow‐up of registry data involving millions of women to assess any relationship between vaccination and autoimmune conditions.
The data indicate that HPV vaccination is most effective in those not already exposed to HPV, supporting the widespread introduction of vaccination programmes aimed at young adolescent girls. Catch‐up vaccination programmes in older girls and young women will have less of a benefit, based on these data. Importantly, some harms of vaccination are likely to be detected over a relatively short period, compared with harms from other medicines, and all but very rare harms would be captured during large randomized controlled trials. A more complete picture of the beneficial effects on CIN and pregnancy outcomes is only likely to be realized over the course of many years. In the case of cervical cancer, the true effects will probably not be evident for one to two decades.
This Cochrane Review answers some important questions with high certainty of evidence. Some questions cannot be answered by this review, including effects on very rare side effects, vaccination of boys, and other, longer‐term HPV‐related cancer outcomes. HPV is known to increase the risk of other cancers, such as vulval and penile cancers, and some head and neck cancers. Such cancers are rarer and take longer to develop. Ascertaining effects of vaccination on these rarer outcomes may require the evaluation of non‐randomized, population‐level evidence over many years.
Cochrane aims to evaluate and present the evidence to decision‐makers, be they governments, healthcare policy makers, parents, or young women. We hope that this review will be used to support policy or personal decision‐making about HPV vaccination that is informed by the best current evidence, balancing facts rather than opinions.
Jo Morrison1, Toby Lasserson2
1Department of Gynaecological Oncology, Musgrove Park Hospital, Taunton, UK
2Editorial & Methods Department, Cochrane, London, UK
How to cite
Jo Morrison, Toby Lasserson. HPV vaccination: balancing facts[editorial]. Cochrane Database of Systematic Reviews 2018;(6): 10.1002/14651858.ED000126
1. Deer B. MMR: the truth behind the crisis. The Sunday Times. 2004 February 22. Available at briandeer.com/mmr/lancet‐deer‐2.htm
2. Arbyn M, Xu L, Simoens C, Martin‐Hirsch PPL. Prophylactic vaccination against human papillomaviruses to prevent cervical cancer and its precursors. Cochrane Database of Systematic Reviews 2018;(5):CD009069. https://doi.org/10.1002/14651858.CD009069.pub3
3. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. International Journal of Cancer 2015;136(5):E359–96. https://doi.org/10.1002/ijc.29210
4. Cancer Research UK. Cervical cancer statistics. www.cancerresearchuk.org/health‐professional/cancer‐statistics/statistics‐by‐cancer‐type/cervical‐cancer (accessed on 25 May 2018)
5. McCredie MR, Sharples KJ, Paul C, Baranyai J, Medley G, Jones RW, et al. Natural history of cervical neoplasia and risk of invasive cancer in women with cervical intraepithelial neoplasia 3: a retrospective cohort study. Lancet Oncology 2008;9(5):425–34. https://doi.org/10.1016/S1470‐2045(08)70103‐7
6. Kyrgiou M, Athanasiou A, Kalliala IEJ, Paraskevaidi M, Mitra A, Martin‐Hirsch PPL, et al. Obstetric outcomes after conservative treatment for cervical intraepithelial lesions and early invasive disease. Cochrane Database of Systematic Reviews 2017;(11):CD012847. https://doi.org/10.1002/14651858.CD012847
7. Kyrgiou M, Mitra A, Arbyn M, Paraskevaidi M, Athanasiou A, Martin‐Hirsch PPL, et al. Fertility and early pregnancy outcomes after conservative treatment for cervical intraepithelial neoplasia. Cochrane Database of Systematic Reviews 2015;(9):CD008478. https://doi.org/10.1002/14651858.CD008478.pub2
8. O’Connor M, Gallagher P, Waller J, Martin CM, O’Leary JJ, Sharp L, et al. Adverse psychological outcomes following colposcopy and related procedures: a systematic review. BJOG 2016;123(1):24–38. https://doi.org/10.1111/1471-0528.13462
9. IARC Working Group on the Evaluation of Carcinogenic Risk to Humans. Human papillomaviruses. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans Vol. 90. Lyon, France: IARC Press; 2007. Available from www.ncbi.nlm.nih.gov/books/NBK321760
10. Munoz N, Bosch FX, Castellsague X, Diaz M, De Sanjose S, Hammouda D. Against which human papillomavirus types shall we vaccinate and screen? The international perspective. International Journal of Cancer 2004;111:278–85. https://doi.org/10.1002/ijc.20244
11. Fang NX, Frazer IH, Zhou J, Fernando GJ. Post translational modifications of recombinant human papillomavirus type 6b major capsid protein. Virus Research 1999;60(2):113–21. https://doi.org/10.1016/S0168‐1702(98)00117‐8
12. Pagliusi SR, Aguado MT. Efficacy and other milestones for human papillomavirus vaccine introduction. Vaccine 2004;23(5):569–78. https://doi.org/10.1016/j.vaccine.2004.07.046
Declarations of interest
The authors have completed the ICMJE form for disclosure of potential conflicts of interest. JM is a gynaecological oncologist and lead colposcopist, responsible for delivering part of the UK National Health Service (NHS) cervical screening programme in her region of the UK. JM treats patients with CIN and cervical cancer but is not involved in vaccination for HPV and does no private work, working full time for the NHS. TL is a paid employee of Cochrane. The authors report no other conflicts of interest.
Provenance and peer review
This editorial was commissioned and was not externally peer reviewed.
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Related Cochrane ReviewsProphylactic vaccination against human papillomaviruses to prevent cervical cancer and its precursors
Marc Arbyn, Lan Xu, Cindy Simoens, Pierre PL Martin‐Hirsch
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